Retinal ganglion cells (RGCs) are the only output neurons that relay visual signals from the eyes to the brain. RGC death is a crucial element in the pathogenesis in many retinal diseases leading to blindness, such as glaucoma and optic nerve injury. These diseases are also the leading causes of blindness of veterans. The prevalence of blinding diseases in veterans is very high and about 20.5-63.4% of veterans were diagnosed with at least one ocular disease. A significant cause of vision defects of VA patients is traumatic optic neuropathy (TON) related to traumatic brain injury (TBI). TBI is a significant cause of death and disability worldwide, and it is estimated 1.6-3.8 million new TBI cases occur in the US each year. About 57-66% veterans with TBI had vision problems and no treatment for TON is more effective than observation. Therefore, the treatment of vision impairment related to TBI is a significant challenge for the VA healthcare system, and it has been limited by incomplete understanding of the molecular mechanisms that mediating the RGC death in these diseases. In addition to the primary injury, secondary injuries dramatically worsen the damage and cause about 40% of TBI deaths. One of the significant secondary injuries of TBI and TON is glutamate excitotoxicity, the pathological process by which neurons are damaged and eventually killed by excessive stimulation of glutamate receptors. This process also plays critical roles in other neurodegenerative diseases, such as glaucoma, which specifically injure RGCs. Therefore, effectively minimizing or preventing glutamate excitotoxicity is crucial to reduce RGCs death and preserve vision. Based on the understanding of the mechanisms which control the vulnerability of RGCs, we plan to develop novel treatment strategies to prevent RGC death in these diseases. Recent studies have shown that immune molecules play essential roles in neuron repair and cell death in CNS diseases. In the retina, the receptors of major histocompatibility complex (MHC) class I molecules, T-cell receptor, (TCR) and their associated proteins are expressed by RGCs. The mutation of these molecules reduced the susceptibility of RGCs to glutamate excitotoxicity and optic nerve crush (ONC). These findings strongly support the possibility that MHCI/TCR could protect RGCs from death. Also, the susceptibility of RGCs to glutamate excitotoxicity and ONC vary significantly among different types of RGC and the types of pathological insults. These results demonstrate that multiple mechanisms regulate the death of RGCs and, therefore, the treatment strategies to prevent RGC death in diseases need to be designed accordingly. In this study, we plan to conduct proof-of-principle studies to establish the role of MHCI-TCR as a critical mediator of neuronal injury induced by glutamate excitotoxicity and ONC. Our preliminary results showed that susceptibility of RGCs to NMDA excitotoxicity and ONC is RGC type-dependent, mutation of CD3z significantly reduces the susceptibility of RGCs, pharmacological inhibition of Src family member, Hck, and ZAP70 protects RGCs, and RGCs express both Hck and ZAP70. We will further determine whether Hck protects RGCs through CD3z activation, whether the protective efficacy of Hck and ZAP70 inhibitors on RGCs is type specific, and whether systemic application of the inhibitors protects RGCs as effective as an intraocular injection (Aim 1). We will also determine whether the protective efficacy of the inhibitors of Hck and ZAP70 on RGCs in ONC is RGC type-dependent (Aim 2). Finally, we will prove the principle of whether the co-application of inhibitors of Hck or ZAP70 with a mGluR1 antagonist protects RGCs synergistically and to establish the optimal strategy for RGC protection (Aim 3). The research will use state-of-art pharmacological, genetic, cellular, imaging, electrophysiological and behavioral approaches, which has several unique advantages: it is grounded in a robust yet entirely novel mechanistic framework built on current neuroscience, it targets multiple ocular injuries and diseases commonly seen in VA patients, and may lead to a novel therapeutic strategy relevant to several eye diseases and TBI in veterans.